Harpagide alleviates neuroinflammation and cognitive dysfunction in sepsis-associated encephalopathy: Association with the MMP9/NF-κB signaling pathway
5 affiliations
- 1The Second Clinical Medical College, Guizhou University of Traditional Chinese Medicine, Guiyang, China
- 2The Second Affiliated Hospital, Guizhou University of Traditional Chinese Medicine, Guiyang, China
- 3Guizhou Provincial People’s Hospital, Guiyang, China
- 4Guizhou Medical University, Guiyang, China
- 5Shanghai Children’s Medical Center Guizhou Hospital, Guiyang, China
Abstract
Background: Sepsis-associated encephalopathy (SAE) is a severe neurological complication of sepsis, characterized by uncontrolled neuroinflammation and cognitive decline, yet no specific therapy is currently available. Harpagide, a naturally occurring iridoid glycoside, has been reported to possess anti-inflammatory and neuroprotective activities; however, its therapeutic potential in SAE remains unexplored. This study aimed to investigate whether Harpagide exerts neuroprotective effects in SAE and to elucidate the underlying molecular mechanisms. Methods: A mouse model of SAE was established by intraperitoneal injection of lipopolysaccharide (LPS, 18 mg/kg). Cognitive performance was assessed using behavioral assays. Brain tissue morphology and neuronal survival were evaluated through histopathological examination. Glial cell activation and the production of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) were measured. Network pharmacology was employed to predict potential targets, followed by molecular docking and molecular dynamics simulations to predict binding interactions with core targets. Western blotting was performed to determine the expression levels of key proteins involved in the MMP9/NF-κB signaling pathway. Results: Treatment with Harpagide significantly improved behavioral performance, ameliorated brain pathological changes, preserved hippocampal neurons, suppressed glial activation, and reduced the levels of TNF-α, IL-1β, and IL-6 in SAE mice. Network pharmacology analysis predicted four core targets: GAPDH, CASP3, MMP9, and ICAM1. Molecular docking and molecular dynamics simulations suggested stable binding between Harpagide and MMP9. Western blot analysis further showed that Harpagide treatment was associated with reduced expression of MMP9 and phosphorylated NF-κB p65 in both hippocampal and cortical tissues. Conclusions: The present study demonstrates that Harpagide exerts neuroprotective effects in SAE, which are associated with mitigated neuroinflammation and reduced MMP9/NF-κB signaling, supporting its potential as a promising therapeutic candidate for this devastating condition.
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BibTeX
@article{lou2026harpagide,
title = {{Harpagide alleviates neuroinflammation and cognitive dysfunction in sepsis-associated encephalopathy: Association with the MMP9/NF-κB signaling pathway}},
author = {Fen Lou and Guochun Deng and Jiejuan Chen and Yijiang Jing and Ao Wang and Mazhong Zhang and Yongping Zhang and Bin Wang},
journal = {PLOS One},
year = {2026},
month = nov,
doi = {10.1371/journal.pone.0362296},
url = {https://doi.org/10.1371/journal.pone.0362296},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Harpagide alleviates neuroinflammation and cognitive dysfunction in sepsis-associated encephalopathy: Association with the MMP9/NF-κB signaling pathway
AU - Fen Lou
AU - Guochun Deng
AU - Jiejuan Chen
AU - Yijiang Jing
AU - Ao Wang
AU - Mazhong Zhang
AU - Yongping Zhang
AU - Bin Wang
PY - 2026
DA - 2026/11/05
JO - PLOS One
DO - 10.1371/journal.pone.0362296
UR - https://doi.org/10.1371/journal.pone.0362296
AB - Background: Sepsis-associated encephalopathy (SAE) is a severe neurological complication of sepsis, characterized by uncontrolled neuroinflammation and cognitive decline, yet no specific therapy is currently available. Harpagide, a naturally occurring iridoid glycoside, has been reported to possess anti-inflammatory and neuroprotective activities; however, its therapeutic potential in SAE remains unexplored. This study aimed to investigate whether Harpagide exerts neuroprotective effects in SAE and to elucidate the underlying molecular mechanisms. Methods: A mouse model of SAE was established by intraperitoneal injection of lipopolysaccharide (LPS, 18 mg/kg). Cognitive performance was assessed using behavioral assays. Brain tissue morphology and neuronal survival were evaluated through histopathological examination. Glial cell activation and the production of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) were measured. Network pharmacology was employed to predict potential targets, followed by molecular docking and molecular dynamics simulations to predict binding interactions with core targets. Western blotting was performed to determine the expression levels of key proteins involved in the MMP9/NF-κB signaling pathway. Results: Treatment with Harpagide significantly improved behavioral performance, ameliorated brain pathological changes, preserved hippocampal neurons, suppressed glial activation, and reduced the levels of TNF-α, IL-1β, and IL-6 in SAE mice. Network pharmacology analysis predicted four core targets: GAPDH, CASP3, MMP9, and ICAM1. Molecular docking and molecular dynamics simulations suggested stable binding between Harpagide and MMP9. Western blot analysis further showed that Harpagide treatment was associated with reduced expression of MMP9 and phosphorylated NF-κB p65 in both hippocampal and cortical tissues. Conclusions: The present study demonstrates that Harpagide exerts neuroprotective effects in SAE, which are associated with mitigated neuroinflammation and reduced MMP9/NF-κB signaling, supporting its potential as a promising therapeutic candidate for this devastating condition.
SN - 1932-6203
ER -